The T cell/transmembrane, immunoglobulin, and mucin (TIM) gene family was positionally cloned in 2001 using a congenic mouse model of asthma. Since that time, a great deal of evidence has accumulated indicating that this gene family plays a critical role in regulating immune responses, including transplant tolerance, autoimmunity, the regulation of allergy and asthma, and the response to viral infections.
The TIM gene family consists of eight members (TIM-1-8) on mouse chromosome 11B1.1, and three members (TIM-1, TIM-3, and TIM-4) on human chromosome 5q33.2, located in a chromosomal region that has been repeatedly linked with asthma, allergy, and autoimmunity. Expression, function, and structural studies confirm that mouse TIM-1, TIM-3, and TIM-4 are the orthologues of human TIM-1, TIM-3, and TIM-4, respectively. TIM genes encode type I cell-surface glycoproteins with common structural features including an N-terminal immunoglobulin (Ig)-like domain, a mucin domain with O-linked glycosylations and with N-linked glycosylations close to the membrane, a single transmembrane domain, and a cytoplasmic region with tyrosine phosphorylation motif(s), except in TIM-4.
TIM-1, TIM-3, and TIM-4 are pattern recognition receptors specialized for recognition of phosphatidylserine (PtdSer). PtdSer is normally localized to the inner leaflet of the plasma membrane but is redistributed and exposed on the outer membrane when a cell undergoes apoptosis. PtdSer on apoptotic cells provides a key signal that triggers cell engulfment. Recognition of apoptotic cells is an essential component of tissue homeostasis and immune regulation.
TIM-1, TIM-3, and TIM-4 differ in molecular structure and expression patterns, suggesting that they have distinct functions in regulating T-cell responses. TIM-1, an important susceptibility gene for asthma and allergy, is preferentially expressed on Th2 cells and functions as a potent costimulatory molecule for T-cell activation. TIM-3 is preferentially expressed on T-helper 1 (Th1) and Tc1 cells and generates an inhibitory signal resulting in apoptosis of Th1 and Tc1 cells. Polymorphisms in TIM-1 and TIM-3 may reciprocally regulate the direction of T-cell responses. TIM-3 is also expressed on some dendritic cells (DCs) and can mediate phagocytosis of apoptotic cells and cross-presentation of antigen. In contrast, TIM-4 is exclusively expressed on antigen-presenting cells (APCs), where it mediates phagocytosis of apoptotic cells and plays an important role in maintaining tolerance. TIM molecules thus provide a functional repertoire for recognition of apoptotic cells, which determines whether apoptotic cell recognition leads to immune activation or tolerance, depending on the TIM molecule engaged and the cell type on which it is expressed.
The development of therapies relating to this gene family is of great clinical interest. The present invention addresses this issue.